Sulfiredoxin-1 accelerates erastin-induced ferroptosis in HT-22 hippocampal neurons by driving heme Oxygenase-1 activation

Ferroptosis, a recently identified non-apoptotic form of cell death, is strongly associated with neurological diseases and has emerged as a potential therapeutic target. Nevertheless, the fundamental mechanisms are still predominantly unidentified. In the current investigation, sulfiredoxin-1 (SRXN1) has been identified as a crucial regulator that enhances the susceptibility to ferroptosis in HT-22 mouse hippocampal cells treated with erastin. Utilizing TMT-based proteomics, a significant increase in SRXN1 expression was observed in erastin-exposed HT-22 cells. Efficient amelioration of erastin-induced ferroptosis was achieved via the knockdown of SRXN1, which resulted in the reduction of intracellular Fe2+ levels and reactive oxygen species (ROS) in HT-22 cells. Notably, the activation of Heme Oxygenase-1 (HO-1) was found to be crucial for inducing SRXN1 expression in HT-22 cells upon treatment with erastin. SRXN1 increased intracellular ROS and Fe2+ levels by activating HO-1 expression, which promoted erastin-induced ferroptosis in HT-22 cells. Inhibiting SRXN1 or HO-1 alleviated erastin-induced autophagy in HT-22 cells. Additionally, upregulation of SRXN1 or HO-1 increased the susceptibility of HT-22 cells to ferroptosis, a process that was counteracted by the autophagy inhibitor 3-Methyladenine (3-MA). These results indicate that SRXN1 is a key regulator of ferroptosis, activating the HO-1 protein through cellular redox regulation, ferrous iron accumulation, and autophagy in HT-22 cells. These findings elucidate a novel molecular mechanism of erastin-induced ferroptosis sensitivity and suggest that SRXN1-HO-1-autophagy-dependent ferroptosis serves as a promising treatment approach for neurodegenerative diseases. •SRXN1 is a positive regulator of ferroptosis in neuronal cells.•In HT-22 cells, inhibiting SRXN1 gene expression suppresses ferroptosis by modulating HO-1 and autophagy pathways.•Targeting the SRXN1-ferroptosis circuit provides a promising therapeutic strategy for treating neurodegenerative diseases.